Chemical compounds

ABSTRACT

The present invention is related to aza-oxindole derivatives, compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US02/30150 filed Sep. 24, 2002, which claims priority from US60/326,012 filed Sep. 27, 2001.

BACKGROUND OF THE INVENTION

The present invention is related to aza-oxindole derivatives,compositions containing the same, and methods of use and manufacture ofthe same. Such compounds generally are useful pharmacologically asagents in those disease states alleviated by the alteration of mitogenactivated signaling pathways in general, and in particular in theinhibition or antagonism of protein kinases, which pathologicallyinvolve aberrant cellular proliferation. Such disease states includetumor growth, restenosis, atherosclerosis, pain and thrombosis. Inparticular, the present invention relates to a series of substitutedaza-oxindole compounds, which exhibit Trk family protein tyrosine kinaseinhibition, and which are useful in cancer therapy and chronic painindications.

Cell growth, differentiation, metabolism and function are tightlycontrolled in higher eukaryotes. The ability of a cell to rapidly andappropriately respond to the array of external and internal signals itcontinually receives is of critical importance in maintaining a balancebetween these processes (Rozengurt, Current Opinion in Cell Biology1992, 4, 161–5; Wilks, Progress in Growth Factor Research 1990, 2,97–111). The loss of control over cellular regulation can often lead toaberrant cell function or death, often resulting in a disease state inthe parent organism.

The protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function (Hanks, et al., Science1988, 241, 42–52). A partial list of such kinases includes ab1, ATK,bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6,cRaf₁, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck,IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,tie₁, tie₂, TRK, Yes, and Zap70.

One of the most commonly studied pathways involving kinase regulation iscellular signaling from receptors at the cell surface to the nucleus(Crews and Erikson, Cell 1993, 74, 215–7). One example of this pathwayincludes a cascade of kinases in which members of the growth factorreceptor tyrosine kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, theInsulin receptor), deliver signals through phosphorylation to otherkinases such as Src tyrosine kinase, and the Raf, Mek and Erkserine/threonine kinase families (Crews and Erikson, Cell 1993, 74,215–7; Ihle, et al., Trends in Biochemical Sciences 1994, 19, 222–7).Each of these kinases is represented by several family members (Pelechand Sanghera, Trends in Biochemical Sciences 1992, 17, 233–8) which playrelated, but functionally distinct roles. The loss of regulation of thegrowth factor signaling pathway is a frequent occurrence in cancer aswell as other disease states.

A variety of evidence suggests that nerve growth factor (NGF) may be amediator of some persistent pain states, including neuropathic andinflammatory pain. For example: a) NGF is rapidly elevated in inflamedtissues; b) NGF specific antibodies substantially diminish inflammatoryhypersensitivity; c) injection of NGF into adult rats causes a profoundhypersensitivity to noxious heat and mechanical stimuli; and d) lowlevel administration of recombinant NGF induces hyperalgesia in healthyhumans. NGF produces hyperalgesia through several potential mechanisms.NGF results in the upregulation of peptide neurotransmitters in neuronsthat detect painful stimuli (nociceptors). NGF increases theexcitability of spinal cord neurons to activation. Mast cells expressNGF receptors and NGF triggers the release of granules containinghistamine and serotonin. Histamine and serotonin are capable ofsensitizing nociceptors. (Wood, John (2000) Pathology of Visceral Pain:Molecular Mechanisms and Therapeutic Implications II. Genetic Aproachesto Pain Therapy. Am. J. Physiol. 278(40), G507–G512.)

NGF binds to two different receptors, the neurotrophin receptor p75(p75NTR) 30 and TrkA. p75NTR is a member of a family of receptors thatincludes tumor necrosis factor receptor (TNFR) and FAS/APO1. Thesereceptors have in common a cysteine-rich motif in the extracellulardomain, a single transmembrane domain, and a cytoplasmic domain. p75NTRsignals in a fashion similar to TNFR and FAS via the activation of NFkB,JNK, and ceramide production. The functional significance of p75NTR inNGF mediated biological responses is not clear. Proposed functionsinclude a) modulation of TrkA driven responses and b) induction of celldeath in cells that express p75NTR, but not TrkA.

TrkA appears to be the primary mediator of NGF driven biologicalresponses. The most compelling evidence for this comes from NGF and TrkAknockout mice. Mice defective in either the ligand or receptor componentof this system have remarkably similar phenotypes. Examples of thesephenotypes include severe sensory defects characterized by a completeloss of nociceptive activity and deficiencies in thermoception.Anatomically these mice exhibit extensive peripheral nervous system cellloss in trigeminal, dorsal root, and sympathetic ganglia. Other evidencefor the involvement of TrkA in NGF driven responses comes from the studyof the PC12 cell line. PC12 cells express high levels of p75NTR andTrkA. NGF causes PC12 cells to differentiate into a neuronal phenotypecharacterized by the development of axonal projections. Loss of TrkAprevents PC12 cells from differentiating in response to NGF. (Eggert, A.et al (2000) Molecular Dissection of TrkA Signal Transduction PathwaysMediating Differentiation in human Neuroblastoma Cells, Oncogene,19(16), 2043–2051.)

There is evidence that Trk tyrosine kinases play a role in thedevelopment of a variety of cancers including, for example, breast andprostate cancer. (Guate, J. L. et al, (1999) Expresion of p75LNGFR andTrk Neurotrophin Receptors in Normal and Neoplastic Human Prostate. BJUInt 84(4), 495–502; Tagliabue, E. et al, Nerve Growth Factor cooperateswith p185HER2 in Activating Growth of Human Breast Carcinoma Cells,(2000) J. Biol Chem. 275(8), 5388–5394.) Further, there is strongevidence that mediation of the Trk kinase signaling will providebeneficial biological effects. (LeSauteur, L et al (1998) Developmentand Uses of Small Molecule Ligands of TrkA Receptors. Adv. Behav. Biol.49, 615–625; Zhu, Z. et al (1999) Nerve Growth Factor ExpressionCorrelates with Perineural Invasion and Pain in Human Pancreatic Cancer,Journal of Clinical Oncology, 17(8), 2419–28; Friess, H. et al, NerveGrowth Factor and its High-Affinity Receptor in Chronic Pancreatitis(1999) Annals of Surgery 230(5), 615–24.)

TrkA is a receptor tyrosine kinase that belongs to a subfamily oftyrosine kinases that includes TrkB, and TrkC. TrkB and TrkC arestructurally similar to TrkA, but respond to different ligands in theneurotrophin family. NGF signaling through TrkA has been bestcharacterized in the PC12 system and is similar to signal transductionmechanisms of other tyrosine kinase receptors. NGF exists as ahomodimer. Binding of NGF promotes dimerization, andautophoshphorylation of TrkA. Phosphorylation of TrkA increases thecatalytic activity of the kinase domain and creates binding sites forSH2 domain containing cytoplasmic proteins. SH2 domain binding eventsinitiate the activation of several signal transduction pathways such asPLCg, ras, PI3 kinase/AKT, and Raf/MEK/ERK. (Frade, J. M. et al, (1998)Nerve growth factor: two receptors, multiple functions, BioEssays 20:137–145; Kaplan, D. R. et al, (1997) Signal transduction by theneurotrophin receptors, Current Opinion in Cell Biology. 9: 213–221;Barbacid, M. (1995) Neurotrophic factors and their receptors, CurrentOpinion in Cell Biology. 7:148–155; Snider, W. D. (1994) Functions ofthe Neurotrophins during nervous system development: What the knockoutsare teaching us, Cell, 77:627–638.)

The selective inhibition of the Trk family of kinases (TrkA, TrkB, andTrkC) is one aspect of the present invention.

There is a continuing need in the medical field for new and moreeffective treatments for cancer and for the relief of pain, especiallychronic pain. Because TrkA and other Trk kinases may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and other Trkkinases may provide an effective treatment for cancer and for chronicpain states. At present, there is an unmet need for small moleculecompounds that may be readily synthesized and are potent inhibitors ofTrkA and other Trk family kinases. The present inventors have nowdiscovered novel aza-oxindole derivative compounds that selectivelyinhibit the catalytic activity of TrkA and/or other Trk family kinasesthereby providing new treatment strategies for those afflicted withcancer and chronic pain. It is additionally possible that inhibitors ofcertain kinases may have utility in the treatment of diseases when thekinase is not misregulated, but is nonetheless essential for maintenanceof the disease state.

SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided compounds ofthe formula (I):

wherein

-   X is N and Z is CH; or-   X is CH and Z is N;-   R is hydrogen or halogen; and-   A is selected from    -   wherein R¹ is halogen,        -   R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, or C₁–C₆            alkylsulfanyl, and;        -   R³ is hydrogen or C₁–C₆ alkyl; and    -   salts, solvates and physiologically functional derivatives        thereof.

Due to the presence of an aza-oxindole exocyclic double bond, alsoincluded in the compounds of the invention are their respective pure Eand Z geometric isomers as well as mixtures of E and Z isomers. Theinvention as described and claimed does not set any limiting ratios onprevalence of Z to E isomers.

Likewise, it is understood that compounds of formula (I) as used hereinincludes all tautomeric forms other than the specific tautomerrepresented by the formula.

Certain of the compounds as described contain one or more chiral, orasymmetric, centers and are therefore capable of existing as opticalisomers that are either dextrorotatory or levorotatory. Also included inthe compounds of the invention are the respective dextrorotatory orlevorotatory pure preparations, and mixtures thereof.

Certain compounds of formula (I) above are optionally provided instereoisomeric forms (e.g. they may contain one or more asymmetriccarbon atoms or may exhibit cis-trans isomerism). The individualstereoisomers (enantiomers and diastereoisomers) and mixtures of theseare included within the scope of the present invention.

The present invention also provides compounds of formula (I) andpharmaceutically acceptable salts thereof (hereafter collectivelyreferred to as the “active compounds”) for use in therapy, andparticularly in the treatment of disorders mediated by a kinase, such asTrkA tyrosine kinase, including, for example, cancers and chronic pain.In a further embodiment, the disorder involves abnormal angiogenesis,such as arthritis, diabetic retinopathy, macular degeneration andpsoriasis.

A further aspect of the invention provides a method of treating adisorder in a mammal, said disorder mediated by inappropriate mitogenactivated kinase activity, including administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate, or physiologically functional derivative thereof. In oneembodiment, the disorder is cancer. In another embodiment the disorderis chronic pain. In a further embodiment, the disorder involves abnormalangiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

In a related aspect the present invention comprises a method forinhibiting a kinase comprising bringing said kinase into contact with acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof.

Another aspect of the present invention provides for the use of acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof, in the preparation of a medicament forthe treatment of a disorder mediated by inappropriate TrkA activity. Inone embodiment, the disorder is cancer. In another embodiment, thedisorder is chronic pain. In a further embodiment, the disorder involvesabnormal angiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

Additionally, compounds of formula (I) or salts, solvates, orphysiologically functional derivatives thereof, can be used in thepreparation of a medicament for the treatment of organ transplantrejection, tumor growth, chemotherapy-induced mucositis,radiation-induced mucositis, plantar-palmar syndrome,chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia,chemotherapy-induced leukopenia and hirsutism or of treating a diseasestate selected from the group consisting of: mucocitis, restenosis,atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis,glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,chronic obstructive pulmonary disease, thrombotic microangiopathy,aglomerulopathy, psoriasis, diabetes mellitus, inflammation, aneurodegenerative disease, macular degeneration, actinic keratosis andhyperproliferative disorders.

Another aspect of the present invention provides the use of an activecompound of formula (I), in co-administration or alternatingadministration with previously known anti-tumor therapies for moreeffective treatment of such tumors.

Other aspects of the present invention related to the inhibition ofprotein kinases are discussed in more detail below.

The inappropriate TrkA activity referred to herein is any TrkA activitythat deviates from the normal TrkA activity expected in a particularmammalian subject. Inappropriate TrkA activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of TrkA activity. Such inappropriate activity mayresult then, for example, from overexpression or mutation of the proteinkinase leading to inappropriate or uncontrolled activation. Furthermore,it is also understood that unwanted TrkA activity may reside in anabnormal source, such as a malignancy. That is, the level of TrkAactivity does not have to be abnormal to be considered inappropriate,rather the activity derives from an abnormal source.

DETAILED DESCRIPTION OF THE INVENTION

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid or by reacting the acid with a suitable organic orinorganic base. Representative salts include the following salts:Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,Clavulanate, Citrate, Diethanolamine, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate,Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine,Oxalate, Pamoate (Embonate), Palmitate, Pantethenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Trifluoroacetate, Triethiodide, Trimethylammonium and Valerate.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of formula (I) and these form a furtheraspect of the invention.

Also included within the scope of the invention are the individualisomers of the compounds represented by formula (I) above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented byformula above as mixtures with isomers thereof in which one or morechiral asymmetric centers are inverted.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon radical having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting ofC₁–C₆ alkyl, C₁–C₆ hydroxyalkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl,C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aryl, aryloxy, heteroaryl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen, or C₁–C₆perfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkyl” as used herein include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl, and the like.

As used herein, the term “C₁–C₆ alkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atoms.Examples of branched or straight chained “C₁–C₆ alkyl” groups useful inthe present invention include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, andisopentyl.

As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon groupwith one or more degrees of unsaturation, having from three to twelvecarton atoms, optionally substituted with substituents selected from thegroup which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. “Cycloalkyl” includes by way of example:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a non-aromatic three to twelve-membered heterocyclic ringbeing saturated or having one or more degrees of unsaturation containingone or more heteroatomic substitutions selected from S, SO, SO₂, O or N,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more of another “heterocyclic” ring(s) or cycloalkyl ring(s).Examples of “heterocyclic” include, but are not limited to,tetrahydrofuran, pyran, 1,4dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, andthe like.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings to form ring systems such asanthracene, phenanthrene and napthalene, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of aryl include, but are not limited to, phenyl,2-naphthyl, 1-naphthyl, biphenyl, and the like.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms atany position, where N-oxides and sulfur monoxides and sulfur dioxidesare permissible heteroaromatic substitutions, optionally substitutedwith substituents selected from the group which includes lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano,halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systems, one ormore of the rings may contain one or more heteroatoms. Examples of“heteroaryl” used herein are furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole andindazole, and the like.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the term “C₁–C₆ alkoxy” refers to analkoxy group as defined herein wherein the alkyl moiety contains atleast 1, and at most 6, carbon atoms. Exemplary C₁–C₆ alkoxy groupsuseful in the present invention include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above and the term “C₁–C₆ alkylsulfanyl”refers to an alkylsulfanyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” is inclusive of circumstances inwhich described condition is present and circumstances in which thedescribed condition is not present, for example, where the term is usedwith reference to a chemical substituent, it indicates the inclusion ofembodiments in which the specified substituent is present as well asembodiments in which the specified substituent is not present.

As used herein, the term “substituted” indicates the presence of thenamed substituent or substituents, and includes multiple degrees ofsubstitution.

As used herein, the terms “contain” or “containing” with reference toalkyl or cycloalkyl substituents indicates in-line substitution(s) withone or more substituents at any position along the alkyl or cycloalkylsubstituents, such as one or more of any of O, S, SO, SO₂, N, orN-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃and so forth.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

The compounds of the present invention have the ability to crystallizein more than one form, a characteristic that is known as polymorphism,and such polymorphic forms (“polymorphs”) are within the scope of thepresent invention. Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.Including within the scope of the term are the terms “biohydrolyzablecarbonate”, “biohydrolyzable ureide”, “biohydrolyzable carbamate”,“biohydrolyzable ester”, and “biohydrolyzable amide”.

As used herein, the terms “biohydrolyzable carbonate”, “biohydrolyzableureide” and “biohydrolyzable carbamate” include carbonates, ureides, andcarbamates, respectively, of a compound of the general formula (I) whichcarbonates, ureides, and carbamates, do not completely diminish thebiological activity of the parent substance. Such carbonates, ureides,and carbamates may confer on the parent compound of the general formula(I) advantageous properties in vivo, such as improved duration ofaction, onset of action, and the like. Also included are compounds whichare relatively biologically inactive but which are converted in vivo bythe subject to the biologically active principle. An advantage of suchbiohydrolyzable forms is that, for example, they facilitate improvedoral administration because the carbonates, ureides, and carbamates aremore readily absorbed from the gut and are then transformed to acompound of formula (I) in plasma. Many examples of such biohydrolyzablecompounds are known in the art and include, by way of example, loweralkyl carbamates.

As used herein, the term “biohydrolyzable ester” is an ester of acompound of general formula, which does not completely diminish thebiological activity of the parent substance. Such esters may confer onthe parent compound of the general formula (I) advantageous propertiesin vivo, such as improved duration of action, onset of action, and thelike. Also included are esters which are relatively biologicallyinactive but which are converted in vivo by the subject to thebiologically active principle. An advantage of such biohydrolyzableforms is that, for example, they facilitate improved oral administrationbecause they are more readily absorbed from the gut and are thentransformed to a compound of formula (I) in plasma. Many examples ofsuch biohydrolyzable esters are known in the art and include, by way ofexample, lower alkyl esters, lower acyloxy-alkyl esters, loweralkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkylesters and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of acompound of general formula, which does not completely diminish thebiological activity of the parent substance. Such amides may confer onthe parent compound of the general formula (I) advantageous propertiesin vivo, such as improved duration of action, onset of action, and thelike. Also included are amides which are relatively biologicallyinactive but which are converted in vivo by the subject to thebiologically active principle. An advantage of such biohydrolyzableforms is that, for example, they facilitate improved oral administrationbecause they are more readily absorbed from the gut and are thentransformed to a compound of formula (I) in plasma. Many examples ofsuch biohydrolyzable are known in the art and include, by way ofexample, lower alkyl amides, α-amino acid amides, alkoxyacyl amides andalkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes compounds, which arehydrolyzable in vivo to yield an active compound of formula (I),including for example, biohydrolyzable amides, biohydrolyzable estersand biohydrolyzable carbamates. The term “prodrug” also includescompounds in which the biohydrolyzable functionality is encompassed inthe compound of formula (I): for example, a lactam formed by acarboxylic group in R₁ and an amine in R₂, and compounds which may beoxidized or reduced biologically at a given functional group to yielddrug substances of formula (I). Examples of such functional groups are,but are not limited to, 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

As used herein, the term “affinity reagent” means a group attached tothe compound of formula (I) which does not affect its in vitrobiological activity, allowing the compound to bind to a target, yet sucha group binds strongly to a third component allowing a) characterizationof the target as to localization within a cell or other organismcomponent, perhaps by visualization by fluorescence or radiography, orb) facile separation of the target from an unknown mixture of targets,whether proteinaceous or not proteinaceous. An Example of an affinityreagent according to b) would be biotin either directly attached to (I)or linked with a spacer of one to 50 atoms selected from the groupconsisting of: C, H, O, N, S, or P in any combination. An Example of anaffinity reagent according to a) above would be fluorescein, eitherdirectly attached to (I) or linked with a spacer of one to 50 atomsselected from the group consisting of: C, H, O, N, S, or P in anycombination.

The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician. The term “therapeutically effective amount”means any amount which, as compared to a corresponding subject who hasnot received such amount, results in improved treatment, healing,prevention, or amelioration of a disease or disorder, or a decrease inthe rate of advancement of a disease or disorder, and also includesamounts effective to enhance normal physiological function.

As used herein, the term “oxo” refers to the substituent═O.

As used herein, the term “halogen” or “halo” shall include —I (iodo),—Br (bromo), —Cl (chloro) and —F (fluoro).

As used herein, the term “mercapto” refers to the substituent —SH.

As used herein, the term “carboxy” refers to the substituent —COOH.

As used herein, the term “cyano” refers to the substituent —CN.

As used herein, the term “aminosulfonyl” refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” refers to the substituent —C(O)NH₂.

As used herein, the term “sulfanyl” refers to the substituent —S—.

As used herein, the term “sulfenyl” refers to the substituent —S(O)—.

As used herein, the term “sulfonyl” refers to the substituent —S(O)₂— or—SO—.

It is to be understood that reference to compounds of formula (I) above,following herein, refers to compounds within the scope of formula (I) asdefined above with respect to X, Z, A, R, R¹, R², and R³ unlessspecifically limited otherwise.

In one embodiment, one of X and Z is nitrogen (N) and the other of X andZ is CH. In one preferred embodiment, X is N and Z is CH. In anotherpreferred embodiment, X is CH and Z is N.

In one embodiment, R is hydrogen, bromo or chloro. In a preferredembodiment, R is hydrogen. In another preferred embodiment, R is bromoor chloro.

In a preferred embodiment, A is

wherein R¹ is halo, preferably bromo or chloro, more preferably bromo,and R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, or C₁–C₆ alkylsulfanyl,preferably C₁–C₆ alkoxy, more preferably methoxy.

In another preferred embodiment, A is

wherein R³ is hydrogen or C₁–C₆ alkyl, preferably methyl.

Highly preferred compounds include:

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula I, as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions which include therapeutically effectiveamounts of compounds of the formula I and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula I and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula I, or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

The compounds of the present invention can be administered in such oral(including buccal and sublingual) dosage forms as tablets, capsules(each including timed release and sustained release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. Likewise, they may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscularinhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.1 to about 100 mg/kg of body weightper day, and particularly about 1 to 10 mg/kg of body weight per day.Oral dosage units will generally be administered in the range of from 1to about 250 mg and more preferably from about 25 to about 250 mg. Thedaily dosage for a 70 kg mammal will generally be in the range of about70 mg to 7 grams of a compound of formula I or II.

The dosage to be administered is based on the usual conditions such asthe physical condition of the patient, age, body weight, past medicalhistory, route of administrations, severity of the conditions and thelike. Oral administration is generally preferred for administration to ahuman. In some cases, a relatively lower dose is sufficient and, in somecases, a relatively higher dose or increased number of doses may benecessary. Topical application similarly may be once or more than onceper day depending upon the usual medical considerations. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. The compounds of the invention can beprepared in a range of concentrations for topical use of about 0.5 toabout 5 mg/ml of suitable solvent. A preferred volume for application tothe scalp is about 2 ml, resulting in an effective dosage delivered tothe patient of about 1 to about 10 mg.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for Example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containingabout 0.01 to about 99.5%, more particularly, about 0.5 to about 90% ofa compound of the formula (II) in combination with a pharmaceuticallyacceptable carrier.

Parenteral administration can be effected by utilizing liquid dosageunit forms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as aqueousoleaginous medium and sterilizing the suspension or solution.

Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservations and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher ester as forExample flavored aqueous solution, while elixirs are prepared throughmyristyl palmitate or mixtures thereof.

Topical formulations of the present invention may be presented as, forinstance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The preferred pharmaceutical compositions are those in a form suitablefor oral administration, such as tablets and liquids and the like andtopical formulations.

The compounds of formula (I) can be prepared readily according to thefollowing reaction General Synthesis Schemes (in which all variables areas defined herein) and Examples or modifications thereof using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants, which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail.

The compounds of the present invention wherein A is a phenyl substituentmay be prepared using Scheme 1. Treatment of 7-azaindole with abrominating agent such as Br₂ under basic aqueous conditions, whichcould include using saturated sodium bicarbonate in water, in a suitablesolvent such as t-butanol will afford the intermediate compound offormula (IV). The selective reduction of the 3,3-dibromines to afford acompound of formula (V) can be achieved via typical reduction conditionssuch as treatment with activated zinc in the presence of saturatedammonium chloride in a suitable solvent such as THF. The mixed aldolcondensation reaction between a compound of formula (V) and (VI) can beused to afford the desired compound of formula II employing conditionssuch as treatment with HCl in a suitable solvent such as acetic acidtypically at elevated temperatures ranging from 50–100 C. One may alsogenerate the appropriately substituted benzaldehydes by treating2-halo-6-substituted phenyl phenols under formylation reactionconditions such as treatment with excess hexamethylenetetramine in asuitable solvent such as acetic acid followed by aqueous acid hydrolysisusing, for example, sulfuric acid in water.

The compounds of the present invention wherein A is an indole substiuentmay be prepared using the synthetic route depicted in Scheme 2.2-Chloro-3-nitropyridine can be used as the starting material togenerate a compound of formula (VII) by treatment with the anion of adimalonate, for example, diethylmalonate prepared using a strong basesuch as sodium hydride in a suitable solvent such as DMSO. Treatment ofa compound of formula (VII) under decarboxylation conditions such asLiCl in a suitable solvent such as water and DMSO may generate theintermediate compound of formula (VIII). The reduction of a compound offormula (VIII) to generate a compound of formula (IX) may be carried outunder multiple conditions, but, by way of example, one could employ anatmosphere of H₂ under 40 psi of pressure in the presence of a catalyticamount of Pd on carbon in a suitable solvent such as ethanol. The “R”groups can be incorporated in the beginning of the synthesis, oralternatively, one could introduce substitution using the intermediatecompound of formula (Xa) where R=H in (X). Scheme 3 depicts a sequenceof reactions to introduce a bromine in the 5-position of the4-aza-oxindole ring system. One skilled in the art may accomplish thisreadily using a bromination reaction such as Br₂ under basic aqueousconditions, which could include using saturated sodium bicarbonate inwater, in a suitable solvent such as t-butanol will afford theintermediate compound of formula (Xl). The selective reduction of the3,3-dibromines to afford a compound of formula (Xb) can be achieved viatypical reduction conditions such as treatment with activated zinc inthe presence of saturated ammonium chloride in a suitable solvent suchas THF. The mixed aldol condensation reaction between a compound offormula (X) and a substituted indole-3-carboxaldehyde can be used toafford the desired compound of formula (III) employing conditions suchas treatment with HCl in a suitable solvent such as acetic acidtypically at elevated temperatures in a range of 50–100C.

The most preferred compounds of the invention are any or all of thosespecifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

Abbreviations used in the Examples are as follows:

g = grams mg = milligrams L = liters mL = milliliters M = molar N =normal mM = millimolar i.v. = intravenous p.o. = per oral s.c. =subcutaneous Hz = hertz mol = moles mmol = millimoles mbar = millibarpsi = pounds per square inch rt = room temperature min = minutes h =hours mp = melting point TLC = thin layer chromatography R_(f) =relative TLC mobility MS = mass spectrometry NMR = nuclear magneticresonance spectroscopy APCI = atmospheric pressure chemical ionizationESI = electrospray ionization m/z = mass to charge ratio t_(r) =retention time Pd/C = palladium on activated carbon ether = diethylether MeOH = methanol Tert-BuOH = tert-butyl alcohol EtOAc = ethylacetate TEA = triethylamine DIEA = diisopropylethylamine THF =tetrahydrofuran DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide DDQ= 2,3-dichloro-5,6-dicyano-1,4-benzoquinone LAH = lithium aluminumhydride TFA = trifluoroacetic acid LDA = lithium diisopropylamide THP =tetrahydropyranyl NMM = N-methylmorpholine, 4-methylmorpholine HMPA =hexamethylphosphoric triamide DMPU = 1,3-dimethypropylene urea d = daysppm = parts per million kD = kiloDalton LPS = lipopolysaccharide PMA =phorbol myristate acetate SPA = scintillation proximity assay EDTA =ethylenediamine tetraacetic acid FBS = fetal bovine serum PBS =phosphate buffered saline solution BrdU = bromodeoxyuridine BSA = bovineserum albumin FCS = fetal calf serum DMEM = Dulbeccols modified Eaglelsmedium pfu = plaque forming units MOI = multiplicity of infection

Reagents are commercially available or are prepared according toprocedures in the literature. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds. ¹H NMR spectra were obtained on VARIAN Unity Plus NMRspectrophotometers at 300 or 400 Mhz. Mass spectra were obtained onMicromass Platform II mass spectrometers from Micromass Ltd. Altrincham,UK, using either Atmospheric Chemical Ionization (APCI) or ElectrosprayIonization (ESI). Analytical thin layer chromatography (TLC) was used toverify the purity of some intermediates which could not be isolated orwhich were too unstable for full characterisation, and to follow theprogress of reactions. Unless otherwise stated, this was done usingsilica gel (Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds, used Merck Silicagel 60 (230–400 mesh), and the stated solvent system under pressure.

EXAMPLE 1 Preparation of3-(3-Bromo-4-hydroxy-5-(2′methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

A solution of 7-azaindole (4.0 g, 34 mmol) in tert-BuOH (200 mL) isstirred at room temperature and pyridinium perbromide (32.5 g, 0.1 mol)is added in portions over 30 min. and the reaction mixture is stirredfor 3 h. Pyridinium perbromide (10.8 g, 33 mmol) is added and themixture is stirred for a further 2 h. The tert-BuOH is evaporated undereduced pressure and the residue is partitioned between water (300 mL)and EtOAc (300 mL). The organic layer is separated and the aqueous layeris extracted with EtOAc. The combined organic layers are washed withwater (2×50 mL), and brine. The organic layer is dried over anhydrousMgSO₄, filtered and the solvent evaporated. Trituration of the residuewith CH₂Cl₂ gives a white solid which is collected by filtration anddried under vacuum to give 3,3-dibromo-7-azaoxindole, 8.35 g. ¹H NMR (d⁶DMSO) 11.99 (s, 1H), 8.21 (dd, 1H, J=5.1, 1.5 Hz), 8.00 (dd, 1H J=7.5,1.5 Hz), 7.17 (dd, 1H, J=7.5, 5.1 Hz). MS (+ve ES) 293 (28), (M+H), 147(100).

ii: 3,3,5 Tribromooxindole

A solution of 3,3-dibromo-7-azaoxindole (5.0 g, 13.4 mmol) in tert-BuOH(100 mL) and water (100 mL) is stirred at room temperature and bromine(5.5 g, 34.3 mmol) is added dropwise over 20 min. A saturated aqueoussolution of sodium bicarbonate (approx. 15 mL) is added dropwise over 30min to raise the pH of the solution to 6.5. The yellow solid formed iscollected by filtration. The filtrate is condensed to approx. 100 mL andextracted with CHCl₃ (2×50 mL). The combined organic extracts are driedover anhydrous magnesium sulfate and the solvent is evaporated underreduced pressure to leave a yellow solid. The solids are combined anddried under vacuum to give 3,3,5 tribromooxindole as a yellow solid,6.25 g (98%). ¹H NMR (CDCl₃) δ 9.4 (br s, 1H), 8.28 (d, 1H, J=2 Hz),7.95 (d, 1H, J=2 Hz).

iii: 5 Bromo-7-azaoxindole

A solution of 3,3,5 tribromooxindole (5.0 g, 13.4 mmol) in fresh THF(100 mL) is stirred at room temperature and a saturated aqueous solutionof ammonium chloride (100 mL) is added. The flask is placed in a waterbath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture isstirred for 20 min and the zinc is removed by filtration through a padof diatomaceous earth. The organic layer is separated and the aqueouslayer is extracted with THF (20 mL). The combined organic layers werewashed with saturated brine solution, dried over anhydrous magnesiumsulfate and the solvent removed under reduced pressure. The brownresidue is triturated with water (20 mL) and the tan solid is collectedby filtration and dried under vacuum to give 5-bromo-7-azaoxindole as atan solid, 2.02 g (71%). ¹H NMR (d⁶ DMSO) δ 11.13 (s, 1H), 8.15 (s, 1H),8.76 (s, 1H), 3.57 (s, 2H). MS (AP −ve) 211 (100) (M−H).

b: Synthesis of 3-(3-Bromo-4-hydroxy-5-(2′methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

A mixture of 0.050 g (0.17 mmol) of 5-bromo-7-aza-oxindole and 0.061 g(0.20 mmol) of 3-bromo-4-hydroxy-5-(2′methoxyphenyl)-hydroxybenzaldehyde(prepared according to the general procedure in Scheme 1: ¹H NMR(DMSO-d₆): δ 9.84 (s, 1H); 8.08 (s, 1H); 7.73 (s, 1H); 7.5 (bs, 1H);7.48 (t, 1H); 7.30 (d, 1H); 7.11 (t, 1H); 7.06 (dd, 1H); 3.89 (s, 3H),APCI 305 (MH+)) was stirred in 1 ml of HOAc. Concentrated HCl (0.50 mL)was added and the mixture was heated to 80° C. for 2 hrs. After coolingto ambient temperature the reaction mixture was diluted with EtOAc. Thesolid was collected by vacuum filtration and washed with EtOAc and Et₂Oto yield3-(3-Bromo-4-hydroxy-5-(2′methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-oneas a yellow solid (0.073 g, 73%): ¹H NMR (DMSO-d₆): δ 11.39 (bs, 1H);(s, 1H); 8.25 (s, 1H); 8.19 (s, 1H); 8.11 (s, 1H); 7.95 (s, 1H); 7.42(m, 2H); 7.23 (m, 2H); 7.10 (m, 2H); 3.93 (s, 3H). APCI (−ve) 501 (M−H).

EXAMPLE 2 Preparation of(3Z)-3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefullywashed with hexanes under nitrogen before the addition of DMSO (115 mL).Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min andthe mixture was stirred for an additional 30 min at room temperature.2–Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction andthe reaction was placed in a pre-heated oil bath set to 100° C. for 15min. The reaction was cooled to room temperature and poured into aqueousammonium chloride (saturated solution, 150 mL). The aqueous solution wasextracted with EtOAc:Hexanes (1:1) four times (200 mL each) and theorganic layers were combined. The organics were concentrated to afford asolid that was recrystallized from a minimal amount of EtOAc:Hexanes(1:1) (12.5 g, 70% yield). APCI MS m/z 281 (M−1).

ii: Ethyl 2-(3-nitro-pyridin-2-yl)-acetate

Diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 0.044 mol) was dissolvedin DMSO (150 mL) and water (0.79 mL, 0.044 mol) and lithium chloride(4.65 g, 0.11 mol) were added at room temperature under nitrogen. Thereaction was warmed to 100° C. 12 h and more lithium chloride (1 g) wasadded to the reaction. The reaction was heated for another 5 hours andcooled to room temperature. Brine (150 mL) was added to the reactionbefore extracting with EtOAc (3×, 275 mL each). The organics werecombined and dried over sodium sulfate, then concentrated in vacuo. Theresulting residue was triturated with diethyl ether and collected byfiltration (8.6 g, 92% yield). 1H NMR 400 MHz (DMSO-d6) 8.83 (m, 1H);8.53 (m, 1H); 7.65 (m, 1H); 4.23 (s, 2H); 4.07 (m, 2H); 1.16 (m, 3H).

iii: Ethyl 2-(3-amino-pyridin-2-yl)-acetate

Under an atmosphere of nitrogen, Pd/C (10%, 1.36 g) was charged to around bottome flask. Ethyl 2-(3-nitro-pyridin-2-yl)-acetate (8.6 g, 0.41mol) was dissolved in ethanol (200 mL) and added to the reaction vessel.The reaction was placed under an atmosphere of hydrogen and stirred atroom temperature for 30 min. The reaction was filtered through celiteand the filtrate was concentrated in vacuo to afford the product as atan solid (6.94 g, 94% yield).

iv: 4-azaoxindole

Ethyl 2-(3-amino-pyridin-2-yl)-acetate (6.94 g, 0.038 mol) was dissolvedin diethyl ether (100 mL) at room temperature. Hydrochloric acid (2M, 35mL) was added and the reaction was stirred for 30 minutes. The volatileswere removed to afford a brown solid that was re-crystallized fromethanol and diethyl ether (4.0 g, 62% yield). 1H NMR 400 MHz (DMSO-d6)12.35 (s, 1H); 8.12 (m, 1H); 7.90 (m, 1H); 7.14 (m, 1H); 5.75 (s, 2H).Electrospray MS m/z 135 (M+1).

b: Synthesis of(3Z)-3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-Methylindole carboxaldehyde (0.020 g, 0.15 mmol), 4-aza-oxindole(0.024 g, 0.15 mmol), acetic acid (1.5 mL) and concentrated HCl (0.4 mL)were combined at room temperature and then warmed to 40 C for 16 hours.Ethyl Acetate (10 mL) was added after the reaction was cooled to roomtemperature and the reddish orange solid that persisted was collected byfiltration. The solids were dried in a vacume oven set to 70 C for 22hours, which afforded an orange solid (0.029 g, 70% yield). 1H NMR 400MHz (DMSO-d6) 8:1 mixture of isomers. 11.39 A(s, 1H), 10.54 B(s,1H),9.98 B(s,1H), 9.69 A(s, 1H), 9.30 A(s, 1H), 8.28 A(m, 1H) 8.28 B(m, 1H),8.23 A(d, 1H), 8.02 B(s, 1H), 7.95 B(d, 1H), 7.67 A(m, 1H), 7.63 A(m,1H), 7.63 B(m, 1H), 7.48 A(m, 1H), 7.42 A(m, 2H), 7.32B(m, 1H), 7.20B(m, 1H), 7.16 B(m, 1H), 4.03 A(s, 3H), 3.99 B(s, 3H). Electrospray MSm/z 276 (M+1).

Prepared in an analogous method to Example 2, except indolecarboxaldehyde was used in place of 1-methylindole carboxaldehyde.Electrospray MS m/z 262 (M+1).

Prepared in an analogous method to Example 2, except 7-aza-oxindole wasused in place of 4-aza-oxindole. Electrospray MS m/z 276 (M+1).

Prepared in an analogous method to Example 2, except 7-aza-oxindole wasused in place of 4-aza-oxindole and indole carboxaldehyde was used inplace of 1-methylindole carboxaldehyde. Electrospray MS m/z 262 (M+1).

Biological Data

The compounds of the present invention have valuable pharmacologicproperties. Different compounds from this class are particularlyeffective at inhibiting the trkA kinase enzyme at concentrations thatrange from 0.0001 to 1 μM and additionally show specificity relative toother kinases. Substrate phosphorylation assays were carried out asfollows:

Screening format: Tyrosine kinase activity is being measured using asynthetic peptide substrate. The enzyme is a GST-fusion of theintracellular domain expressed in SF9 cells. The enzyme is expressed andpurified by Regeneron. The enzyme is preincubated with cold ATP and Mgto allow autophosphorylation prior to running the screen. This increasesthe initial rate of catalysis approximately 3 fold. The assay isperformed in 96 well microtitre plates, and reaction products aredetected following filtration through millipore p81 phosphocelluloseplates.

Assay Conditions

Peptide substrate Src peptide, NH2- RRRAAAEEIYGEI- NH2 Peptide Km 60 uMATP Km 30 uM Kcat/Km (peptide): 1 × 10⁴ Assay conditions 20–40 nM TrkA,30 uM ATP, 50 uM Src peptide, 50 mM MOPS pH 7.5, 10 mM MgCl², 0.6 uCi³³P□ATP Incubation RT for 120′ Termination Add 100 ul of 0.5% Phosphoricacid. Spot 100 ul onto millipore p81 96 well filter plate. Filter, wash3x with 200 ul 0.5% phosphoric acid. Add 50 ul scintillation cocktail.Count in Packard TopcountRepresentative results are shown in Table 1 for the TrkA tyrosine kinaseinhibition

TABLE 1 Substrate Phosphorylation Example TrkA 1 +++ 2 +++ 3 ++ 4 +++ 5+++ IC₅₀ values Symbol <0.010 uM +++ 0.010–0.25 uM ++  0.25–2.5 uM + >2.5 uM − Not determined ND

Utility of Invention

Inhibitors of Trk tyrosine kinase have utility as agents in thetreatment of a wide variety of disorders. These include, for example,cancers and chronic pain.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for cancerconditions, or for other indications for the compounds of the inventionas indicated above. Likewise, the specific pharmacologic responsesobserved may vary according to and depending upon the particular activecompound selected or whether there are present certain pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention. It is intended, therefore, that the invention be limited onlyby the scope of the claims, which follow, and that such claims beinterpreted as broadly as is reasonable.

The application of which this description and claim(s) forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, formulation, process or use claims and may include, by way ofexample and without limitation, one or more of the following claim(s).

1. A compound of the formula (I):

wherein X is CH and Z is N; R is hydrogen or halogen; and A is selectedfrom

wherein R¹ is halogen, R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, orC₁–C₆ alkylsulfanyl, and; R³ is hydrogen or C₁–C₆ alkyl; or salts orsolvates thereof.
 2. A compound as claimed in claim 1, wherein R ishydrogen, bromo or chloro.
 3. A compound as claimed in claim 1, whereinA is,

and R¹ is halogen and R² is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, orC₁–C₆ alkylsulfanyl.
 4. A compound as claimed in claim 1, wherein A is,

wherein R³ is hydrogen or C₁–C₆ alkyl.
 5. A compound selected from:


6. The compound: (3Z)-3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one or salts or solvates thereof.7. The compound:(3Z)-3-[(1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneor salts or solvates thereof.